Defects of the CNS remain the leading cause of death for infants under the age of one year. To understand the basis of such congenital malformations, the processes that underlie normal development must be fully understood. Only then can we conceivably be able to design therapeutic regimes to reduce the prevalence of developmental abnormalities. The mammalian brain is dominated by the cerebral cortex. Yet the complexities of its development as well as its structural and functional organization are just beginning to be revealed. Cells divide, migrate, differentiate axons and dendrites, express neuropeptides and neurotransmitters and establish synaptic contacts as maturation unfolds. By concentrating on analyzing the development of the earliest neurons to migrate and begin to form the cortex of embryonic mice, the proposed studies will clarify the time of origin and subsequent developmental fate of these cells, their interactions with afferents to the cortex, their cellular milieu during migration and some of their unique molecular phenotypes. These cells represent the initial framework that provides a structural organization fundamental for the numerous subsequent waves of migrating neurons that comprise the cortical plate. In addition, the availability of the unique genetic mutant mouse, reeler, presents a singular opportunity to determine the effect that early generated, but malpositioned cortical neurons have on ingrowing axons. Morphological, immunocytochemical and ultrastructural techniques will be used to study these first cortical neurons, their growing neurites, and their afferent axons in cerebral cortex of normal and mutant littermates during maturation. Advances in the understanding of the structural and molecular composition of prenatal cells and axons involved in the determination of the complex but elegant organization of the cerebral cortex in normal and abnormal development will increase our knowledge about development disorders that affect the vulnerable fetal brain.